An O-arylmethylene- or O-(hetero ring-methylene)-substituted tyrosine compound (sometimes to be abbreviated simply as an O-substituted tyrosine compound in the present specification) is useful as an intermediate for the production of, for example, a somatostatin secretion inhibitor as a pharmaceutical agent, and the like (e.g., Journal of Medicinal Chemistry, US, vol. 46, pp. 2334–2344 (2003)).
As a production method of an O-substituted tyrosine compound, for example, methods (1)–(3) shown below, and the like can be mentioned.    (1) WO 02/24625 discloses a method comprising reacting tyrosine with benzyl chloride, in the presence of CuSO4, under basic conditions:
wherein Bn is a benzyl group.
The above-mentioned method achieves a reaction yield of less than 70% and cannot produce O-substituted tyrosine in a high yield. It has been found that, when a halide of a nitrogen-containing compound (e.g., 2-picolyl chloride (i.e., pyridin-2-ylmethylene chloride) and the like) is used instead of benzyl chloride, the reaction proceeds but, since copper is chelated to nitrogen atom in the resulting product and the chelation cannot be solved at a neutral point (pH=7), the reaction yield further decreases. Therefore, the above-mentioned method is unsuitable for production of an O-substituted tyrosine compound with a substituent containing hetero atom, such as nitrogen atom and the like, and poor in versatility.    (2) Tetrahedron Asymmetry, UK, vol. 13, No. 16, pp. 1733–1741 (2002) discloses a method comprising reacting tyrosine, wherein both amino group and carboxyl group are protected, with benzyl bromide, in the presence of K2CO3 or Cs2CO3, using acetone as a solvent:
wherein Boc is a tert-butoxycarbonyl group, Me is a methyl group and Bn is a benzyl group.
The above-mentioned method is generally used as a production method of an O-substituted tyrosine compound in a high yield and widely applicable to other substituents.
However, since the above-mentioned method requires, for example, purification by column chromatography to remove BnBr used in excess and by-products, and further requires protection and deprotection steps of the amino group and the carboxyl group of tyrosine, which increases the number of steps and is complicated. In fact, the carboxyl group is methyl-esterified, then the amino group is protected with Boc, the hydroxyl group is subjected to the benzylation, then the protected carboxyl group is deesterified, and the protected amino group is deprotected to give O-benzyl substituted tyrosine. Therefore, this method is not superior in productivity.    (3) Journal of Chemical Society Parkin Transaction 1, UK, vol. 3, pp. 653–658 (1990) discloses a method comprising reacting an amino-protected tyrosine with bromobenzyl compound (Bn-Br), in the presence of sodium hydride (NaH), using N,N-dimethylformamide (DMF) as a solvent:
wherein Boc is a tert-butoxycarbonyl group and Bn-Br is 4-(methylthio)benzyl bromide.
DMF to be used as a solvent in the above-mentioned method is expensive, dangerous, highly toxic and is not generally suitable for the industrial production of an O-substituted tyrosine compound.
In addition, DMF has a high boiling point (153° C.) and removal of DMF solvent after the completion of the reaction is not industrially easy. Without removal of the solvent, the yield of crystal precipitation to give an object product decreases.
Moreover, a bromo compound (Bn-Br) to be used for the above-mentioned method is expensive and economically unpreferable. When an economical chloro compound (Bn-Cl) is used as an alternative, the reactivity thereof is lower than the bromo compound, and the reaction does not proceed enough. Thus, these methods have been found to be poor in versatility.
In the above-mentioned method, NaH difficult to handle even in an oil dispersion is used in a powder state, and therefore, the above-mentioned method is highly dangerous and is not suitable for the industrial production.
In the above-mentioned conventional art, method (1) poses problems in the yield, productivity and versatility, method (2) requires many steps and difficult purification and has a problem in productivity. The method (3) uses NaH problematic in safety, and expensive DMF as a solvent, posing a problem in economic aspect. Furthermore, method (3) poses problems of difficult removal of DMF after the completion of the reaction, and the like.
Accordingly, there is a high demand in this field for a production method of an O-substituted tyrosine compound, which is superior in productivity, versatility and safety, and useful economically and industrially.